Is CIC p.Ser2504Pro (c.7510T>C) pathogenic?

CIC p.Ser2504Pro (c.7510T>C) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2019-05-28). AlphaMissense: likely benign (0.0898); Common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele; Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Ser2504Pro (c.7510T>C)?

CIC p.Ser2504Pro (c.7510T>C) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

What do computational predictors say about CIC p.Ser2504Pro (c.7510T>C)?

AlphaMissense predicts likely benign (score 0.0898) — an in-silico prediction, not a clinical call.

CIC p.Ser2504Pro

Q: How common is CIC p.Ser2504Pro (c.7510T>C) in the general population?

CIC p.Ser2504Pro (c.7510T>C) is common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7510T>C · rs745695673 · VCV252693

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0898 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
AlphaMissense	0.0898	likely benign
REVEL	0.293	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.4, phastCons 1
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S1595P vs ClinVar S2504P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.81% African / African-American · 1,583/20,278 alleles

Filtering AF 7.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.36%

Overall 3.51% 11,004/313,768 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	14.9%	7
African / African-Americangrpmax	7.81%	13
Admixed American	4.08%	25
European (non-Finnish)	3.62%	28
Ashkenazi Jewishnot grpmax-eligible	3.39%	29
Finnishnot grpmax-eligible	2.96%	34
Middle Eastern	2.81%	36
Remaining individualsnot grpmax-eligible	2.32%	43
South Asian	1.55%	64
East Asian	1.55%	65

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CIC
Protein: p.Ser2504Pro
Coding: c.7510T>C
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs745695673
Type: single nucleotide variant
Location: chr19:42295147 (GRCh38)
Structure: AlphaFold pLDDT 75.09

Full CIC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC c.3179+1G>T Pathogenic ★★ same condition
CIC c.5903-2A>G Likely pathogenic ★★ same condition
CIC p.Asn1136Ser Likely pathogenic ★★ same condition
CIC p.Gln1134Ter Pathogenic ★★ same condition
CIC p.Gln1799Ter Likely pathogenic ★★ same condition
CIC p.Ala1761Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala2064Thr Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cic-p-ser2504pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown